WO2002014306A1

WO2002014306A1 - Process for the preparation of imidazopyridines

Info

Publication number: WO2002014306A1
Application number: PCT/EP2000/008021
Authority: WO
Inventors: Max Rey; Armin RÖSSLER; Giusep Derungs; Jae-Kyoung Pak
Original assignee: Cilag AG
Current assignee: Cilag AG
Priority date: 2000-08-17
Filing date: 2000-08-17
Publication date: 2002-02-21
Anticipated expiration: 2003-02-17
Also published as: ATE262526T1; US6841679B2; CA2417821A1; SK1012003A3; AU2002212143A1; JP2004506634A; US20040072861A1; CZ294416B6; DE60102478D1; WO2002014316A1; AU2000264428A1; CZ2003321A3

Abstract

A compound of general formula (1), in which Y denotes hydrogen, a halogen or a C1-4 alkyl group X1 and X2 denote, independently of each other, hydrogen, a halogen or a C1-4 alkoxy, C1-6 alkyl, CF3, CH3S CH3SO2 or NO2 group and R1 and R2 denote independently of each other, hydrogen or a C1-5 alkyl group, with the proviso that R1 and R2 do not both denote hydrogen, or a salt thereof is prepared by a multi-step process, the last step of which comprises reducing a compound of general formula (6), in which Y, X1, X2, R1 and R2 are as defined above with an appropriate reducing agent, such as Zn, and, if desired, converting the compound of formula (1) thus obtained, into a salt. The product of this process are known to have useful pharmacological properties, e.g. as anxiolytics.

Description

PROCESS FOR THE PREPARATION OF I IDAZOPYRIDINES

The present invention relates to a process for preparing imidazopyridin s of the general formula (1)

in which:

Y denotes hydrogen, a halogen or a C _₄ alkyl group,

X_x and X₂ denote, independently of each other, hydrogen, a halogen or a C_x_₄ alkoxy, C _₆ alkyl, CF₃, CH₃S, CH₃S0₂ or N0₂ group and

R_x and R₂ denote, independently of each other, hydrogen or a C₁__s alkyl group, with the proviso that R_x and R₂ do not both denote hydrogen, or salts thereof.

The products of this process are known to have useful pharmacological properties, e.g. as anxiolytics, see European Patent No. 0 050 563. A process for preparing compounds of formula 1 is described in US Patent No. 4,794,185, Dec. 12, 1988.

The present invention relates to a more efficient process for preparing compounds of formula (1) .

In accordance with the present invention, compounds of the general formula (1) can be prepared by reacting a compound of the general formula (2)

in which Y, X_x and X₂, are as defined above with a compound of the general formula (3)

in which:

A denotes a halogen and B denotes a halogen, a C_x_₄ alkoxy group or an NR_XR ₂ group in which R and R₂ are as defined above to form a compound of the general formula (4)

in which Y, X_x, X₂ and B are as defined above, and, if B denotes a halogen or a C_x.₄ alkoxy group, reacting the compound of the general formula (4) with a compound of the general formula (5)

in which R_x and R₂ are as defined above to form a compound of the general formula (6)

in which Y, X_{l t} X₂, R_x and R₂ are as defined above.

To form a compound of formula (1) , the compound of formula (6) can be treated with a reducing agent If desired, the compound of formula (1) thus obtained is converted into a salt .

It will be appreciated that if in formula (3) B denotes an NR_XR ₂ group in which R₁ and R₂ are as defined above, compound (6) instead of compound (4) is formed directly by reaction of compound (2) with compound (3) .

As set forth above compound (6) is prepared by reacting an imidazopyridine of formula (2) with an oxalic acid derivative of formula (3) . This reaction is conveniently carried out in an aprotic organic solvent, for example n- hexane, cyclohexane, acetonitrile, acetone, ethylacetate, toluene, methyl tert. butyl ether or mixtures of these solvents, preferably a mixture of cyclohexane with toluene, at a temperature range from 0-100° C, preferably from 0- 10°C, and in the presence of an organic base, for example tertiary alkylamines, pyridine or substituted pyridines, preferably pyridine. If in formula (3) B denotes a halogen or a C₁.₄ alkoxy group, the product (4) thus obtained is subsequently reacted with a primary or secondary amine of formula (5) , conveniently at a temperature range from 0- 100°C, preferably from 30-40°C. If in formula (3) B denotes an NR_XR₂ group, the reaction of compound (2) with compound (3) directly yields a compound of formula (6) instead of compound (4) , and no intervening treatment with a compound of formula (5) is necessary. The compound of formula (6) thus obtained is then reacted with an appropriate reducing agent to form compound (1) . This reaction is conveniently carried out in a polar aprotic solvent, for example pyridine, dimethylformamide or acetonitrile, preferably pyridine, in the presence of an organic acid, for example acetic acid, formic acid or toluenesulfonic acid, preferably acetic acid, and of an acylating agent, for example acetic anhydride or acetylchloride, preferably acetic anhydride, at a temperature range from 25-75°C, preferably from 50-55°C. A suitable reducing agent is, for example, Zn.

The compounds of the general formula (6) and their preparation also form part of the present invention.

The following examples illustrate the invention in greater detail .

EXAMPLE 1

Preparation of 6-methyl-N,N-dimethyl-2- (4- methylphenyl) imidazo [1, 2-a]pyridine-3-glyoxyacetamide, compound (6)

To a slurry of 10.0 g (45 mmol) of 6-methyl-N,N-dimethyl-2- (4-methylphenyl) imidazo [1, 2-a] pyridine in a mixture of 20.0 g of toluene and 28.0 g of cyclohexane were added 8.6 (0.068 mmol) of oxalylchloride within 15 minutes at 0-5°C. 3.6 g (45 mmol) of pyridine were added within 5 minutes at 0-5°C. The resulting slurry was heated to 65-70°C and stirred for 2 hours. Then it was cooled to 30-35°C and 8.4 g (187 mmol) of dimethylamine were introduced. To the slurry were added 26.0 g of water and 2.3 g of isopropanol . The product was isolated by filtration to afford the title compound in 80 % yield. EXAMPLE 2

Preparation of N,N-dimethyl-2- [6-methyl-2- (4- methylphenyl) imidazo [1, 2-a] pyridine-3-yl] acetamide, compound (1)

To a slurry of 150.0 g (0.467 mol) of 6-methyl-N,N- dimethyl-2- (4-methylphenyl) imidazo [1, 2-a] yridine-3 - glyoxyacetamide and 105.0 g (1.605 mol) of zinc powder in 443.0 g of pyridine was added a solution of 94.0 g (0.920 mol) of acetic anhydride in 472.5 g of acetic acid within 20 - 25 minutes at a temperature below 45°C. The suspension was then heated to 50-55°C and stirred for 25-30 hours. Unreacted zinc was filtered off and the filtrate was subjected to a vacuum distillation. To the remaining oil 455.0 g of 25% aqueous ammonia solution were added. The precipitated solid was collected by filtration and purified by recrystallization in 800.0 g of methylisobutylketone . The title compound was afforded in 65.6 % yield.

Claims

CLAIMS :

1. A process for preparing compounds of the general formula (6)

in which:

Y denotes hydrogen, a halogen or a C^ alkyl group _x and X₂ denote, independently of each other, hydrogen, a halogen or a C_x_₄ alkoxy, ^ alkyl, CF₃, CH₃S, CH₃S0₂ or N0₂ group and

R and R₂ denote, independently of each other, hydrogen or a C-_L.₅ alkyl group, with the proviso that R and R₂ do not both denote hydrogen,

which process comprises reacting a compound of the general formula (2)

(3)

V

in which: A denotes a halogen and B denotes a halogen, a C_x.₄ alkoxy group or an NR_XR ₂ group in which R_x and R₂ are as defined above to form a compound of the general formula (4)

in which Y, X_x X₂ and B are as defined above and, if B denotes a halogen or a C_α_₄ alkoxy group, reacting the compound of formula (4) with a compound of the general formula (5)

r

H—N<^ (5)

R₂

in which R_x and R₂ are as defined above

2. A compound of the general formula (6)

in which:

Y denotes hydrogen, a halogen or a C^ alkyl group

X and X₂ denote, independently of each other, hydrogen, a halogen or a C^ alkoxy, C __β alkyl, CF₃, CH₃S, CH₃S0₂ or N0₂ group and R₁ and R₂ denote independently of each other, hydrogen or a C ._s alkyl group, with the proviso that R and R₂ do not both denote hydrogen.

3. A process for preparing a compound of the general formula (1)

in which:

Y denotes hydrogen, a halogen or a C_x.₄ alkyl group

X_x and X₂ denote, independently of each other, hydrogen, a halogen or a C_x_₄ alkoxy, C_x._ε alkyl, CP₃, CH₃S CH₃S0₂ or N0₂ group and

R_± and R₂ denote independently of each other, hydrogen or a

Ci-_s alkyl group, with the proviso that R₁ and R₂ do not both denote hydrogen, or a salt thereof which process comprises reducing a compound of the general formula (6)

in which Y, X₁₇ X₂, R_x and R₂ are as defined above with an appropiate reducing agent and, if desired, converting the compound of formula (1) thus obtained into a salt .

4. A process according to claim 3 wherein the reducing agent is Zn .

5. A process according to claim 3 or claim 4 wherein the reduction is carried out in pyridine, dimethylformamide, dimethylacetamide, acetonitrile or a derivative of any of these, in the presence of acetic acid, formic acid or toluenesulfonic acid and of an acylating agent .

6. A process according to claim 5 wherein the acylating agent is acetic anhydride or acetylchloride .